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Dissecting Innate Immune Signaling in Viral Evasion of Cytokine Production
Published on: March 2, 2014
Structural and biological basis of CTL escape in coronavirus-infected mice
Noah S Butler1, Alex Theodossis, Andrew I Webb
1Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
Abstract:
Cytotoxic T lymphocyte escape occurs in many human infections, as well as mice infected with the JHM strain of mouse hepatitis virus, which exhibit CTL escape variants with mutations in a single epitope from the spike glycoprotein (S510). In all CTL epitopes prone to escape, only a subset of all potential variants is generally detected, even though many of the changes that are not selected would result in evasion of the T cell response. It is postulated that these unselected mutations significantly impair virus fitness. To define more precisely the basis for this preferential selection, we combine x-ray crystallographic studies of the MHC class I (D(b))/S510 complexes with viral reverse genetics to identify a prominent TCR contact residue (tryptophan at position 4) prone to escape mutations. The data show that a mutation that is commonly detected in chronically infected mice (tryptophan to arginine) potently disrupts the topology of the complex, explaining its selection. However, other mutations at this residue, which also abrogate the CTL response, are never selected in vivo even though they do not compromise virus fitness in acutely infected animals or induce a significant de novo CTL response. Thus, while structural analyses of the S510/D(b) complex provide a strong basis for why some CTL escape variants are selected, our results also show that factors other than effects on virus fitness limit the diversification of CD8 T cell epitopes.
Insights
Cytotoxic T lymphocyte (CTL) escape variants arise from mutations in viral epitopes. While some mutations are selected for disrupting viral fitness, others are not, indicating factors beyond fitness influence CTL epitope diversification.
Area of Science:
- Immunology
- Virology
- Structural Biology
Background:
- Cytotoxic T lymphocyte (CTL) escape is a mechanism viruses use to evade immune responses.
- Mutations in viral epitopes, such as in the JHM strain of mouse hepatitis virus spike glycoprotein (S510), lead to CTL escape variants.
- Only a subset of potential escape mutations are observed in vivo, suggesting factors beyond immune evasion influence their selection.
Purpose of the Study:
- To investigate the structural and functional basis for the preferential selection of specific CTL escape mutations.
- To understand why certain mutations that abrogate CTL recognition are not selected in vivo.
Main Methods:
- X-ray crystallography was used to study the structure of the MHC class I (D(b))/S510 complex.
- Viral reverse genetics was employed to analyze mutations in the S510 epitope.
- In vivo and in vitro experiments assessed viral fitness and CTL responses.
Main Results:
- A common escape mutation (Trp to Arg at position 4) in the S510 epitope was shown to disrupt the MHC class I (D(b))/S510 complex topology, explaining its selection.
- Other mutations at the same residue also abrogated CTL recognition but were not selected in vivo.
- These unselected mutations did not compromise viral fitness in acute infections or induce a de novo CTL response.
Conclusions:
- Structural disruption of the MHC class I/epitope complex explains the selection of certain CTL escape variants.
- Factors other than viral fitness and immune evasion potential limit the diversification of CD8 T cell epitopes.
- Understanding these limitations is crucial for predicting viral evolution during infections.
